Effect of Prenatal Glucocorticoid Exposure on Circadian Rhythm Gene Expression in the Brains of Adult Rat Offspring

Abstract

Circadian clocks control many vital aspects of physiology from the sleep-wake cycle to metabolism. The circadian clock operates through transcriptional-translational feedback loops. The normal circadian signaling relies on a ‘master clock’, located in the suprachiasmatic nucleus (SCN), which synchronizes peripheral oscillators. Glucocorticoid receptor (GR) signaling has the ability to reset the phase of peripheral clocks. It has been shown that maternal exposure to glucocorticoids (GCs) can lead to modification of hypothalamic-pituitary-adrenal (HPA) function, impact stress-related behaviors, and result in a hypertensive state via GR activation. We previously demonstrated altered circadian rhythm signaling in the adrenal glands of offspring exposed to the synthetic GC, dexamethasone (Dex). Results from the current study show that prenatal exposure to Dex affects circadian rhythm gene expression in a brain region-specific and a sex-specific manner within molecular oscillators of the amygdala, hippocampus, paraventricular nucleus, and prefrontal cortex, as well as the main oscillator in the SCN. Results also show that spontaneously hypertensive rats (SHR) exhibited dysregulated circadian rhythm gene expression in these same brain regions compared with normotensive Wistar-Kyoto rats (WKY), although the pattern of dysregulation was markedly different from that seen in adult offspring prenatally exposed to GCs.

Astrocytes in the mouse suprachiasmatic nuclei respond directly to glucocorticoids feedback

“…This is an essential piece of evidence that might improve the understanding on how the circadian system adapts to jetlag or shift work. Our findings also suggest that the previously observed GCs-dependent modulation of light entrainment 25,53 , locomotor activity 54 and the cellular/molecular changes 44,55,56 , might also be a result from direct GCs feedback to the SCN.…”

Case Report: A novel KNCH2 variant-induced fetal heart block and the advantages of fetal genomic sequencing in prenatal long-term dexamethasone exposure

“…In experimental animals, pulmonary fibrosis, osteoporosis, long bone growth impairment, and neonatal hypoglycemia were identified following prenatal DEX exposure ( Rivet et al, 2022 ; Wu et al, 2022 ; Xie et al, 2022 ; Zhang et al, 2022 ). Mechanistically, circadian rhythms, insulin-like growth factor 1 signaling, angiotensin II signaling, histone modifications, and dysregulation of miRNAs were responsible for long-term adverse presentations following DEX exposure ( Han et al, 2022 ; Liu et al, 2022 ; Madhavpeddi et al, 2022 ; Murray et al, 2022 ; Qiu et al, 2022 ). Thus, the benefits from prenatal DEX administration for autoimmune antibody-negative patients are still being debated.…”

The molecular mechanisms in prenatal drug exposure-induced fetal programmed adult cardiovascular disease

“… Madhavpeddi et al (2022 ) demonstrated the involvement of angiotensin II in sex-selective cardiovascular function and autonomic changes in adult offspring exposed to DEX during the last 4 days of gestation in rats, which influenced the heart rate, heart rate variability, and mean arterial pressure. Murray et al (2022 ) indicated that prenatal exposure to DEX would affect circadian rhythm gene expression and impair the related molecular oscillators. Prenatal betamethasone therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences.…”